2007 SwissTB Award
Dr. Corinne Loeuillet
The tubercle bacillus is one of the major scourges afflicting mankind, causing respectively 8 million cases and 2 million deaths yearly. It has evolved to adopt an intracellular lifestyle, by which it is able to survive precisely within the cells ("phagocytes") devoted to kill bacteria. In so doing, it can survive in the host for its lifetime, fending off its immune responses. Thus, one third of the world population is infected by this bacterium. In the present paper, it is shown not only that the tubercle bacillus can survive within the phagocyte hostile environment, but also that is has acquired the capacity to trigger innate immune reponses, subverting it to make its host cell impervious to acquired immune responses, thus preserving its ecological niche. In other words, the tubercle bacillus steals a weapon from the immune system, turning it against the effectors of acquired immunity as a defense mechanism.
Abstract: The macrophage is the niche of the intracellular pathogen Mycobacterium tuberculosis. Induction of macrophage apoptosis by CD4+ or CD8+ T cells is accompanied by reduced bacterial counts, potentially defining a host defense mechanism. We have already established that M. tuberculosis-infected primary human macrophages have a reduced susceptibility to Fas ligand (FasL)- induced apoptosis. To study the mechanisms by which M. tuberculosis prevents apoptotic signaling, we have generated a cell culture system based on PMA- and IFN-γ-differentiated THP-1 cells recapitulating the properties of primary macrophages. In these cells, nucleotide-binding oligomerization domain 2 or TLR2 agonists and mycobacterial infection protected macrophages from apoptosis and resulted in NF-κB nuclear translocation associated with up-regulation of the antiapoptotic cellular FLIP. Transduction of a receptor-interacting protein-2 dominant-negative construct showed that nucleotide-binding oligomerization domain 2 is not involved in protection in the mycobacterial infection system. In contrast, both a dominant-negative construct of the MyD88 adaptor and an NF-κB inhibitor abrogated the protection against FasL-mediated apoptosis, showing the implication of TLR2-mediated activation of NF-κB in apoptosis protection in infected macrophages. The apoptosis resistance of infected macrophages might be considered as an immune escape mechanism, whereby M. tuberculosis subverts innate immunity signaling to protect its host cell against FasL+-specific cytotoxic lymphocytes.
Mycobacterium tuberculosis subverts innate immunity to evade specific effectors
Corinne Loeuillet1, Fabio Martinon2, Cynthia Perez1, Miguel Munoz1, Margot Thome2 and Pascal R. Meylan1, 3
1 Institut de Microbiologie, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, 2 Département de Biochimie, Universite´ de Lausanne, Lausanne, Switzerland and 3Service des Maladies Infectieuses, Centre Hospitalier Universitaire Vaudois,